Transdermal drug administration device

ABSTRACT

A transdermal drug administration device comprising a drug delivery element ( 10 ) defining a contact surface ( 12 ) for location, in use, against a patient&#39;s skin. The drug delivery element ( 10 ) includes a sustained-release pharmaceutical composition. The composition comprises a network of a carrier material having a high mechanical strength and an active pharmaceutical ingredient. The active pharmaceutical ingredient is co-formedly interspersed within pores in the solid, continuous network of the carrier material.

FIELD OF THE INVENTION

The invention relates to a new transdermal drug administration deviceincluding a non-abusable pharmaceutical composition that provides forthe controlled release of active ingredients, such as opioid analgesics,for transdermal administration.

BACKGROUND

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or common generalknowledge.

Opioids are widely used in medicine as analgesics, for example in thetreatment of patients with severe pain, chronic pain or to manage painafter surgery. Indeed, it is presently accepted that, in the palliationof more severe pain, no more effective therapeutic agents exist.

The term “opioid” is typically used to describe a drug that activatesopioid receptors, which are found in the brain, the spinal chord and thegut. Three classes of opioids exist:

-   (a) naturally-occurring opium alkaloids. These include morphine and    codeine;-   (b) compounds that are similar in their chemical structure to the    naturally occurring alkaloids. These so-called semi-synthetics are    produced by chemical modification of the latter and include the    likes of diamorphine (heroin), oxycodone and hydrocodone; and-   (c) truly synthetic compounds such as fentanyl and methadone. Such    compounds may be completely different in terms of their chemical    structures to the naturally-occurring compounds.

Of the three major classes of opioid receptors (μ, κ and δ), opioids'analgesic and sedative properties mainly derives from agonism at the μreceptor.

Opioid analgesics are used to treat severe, chronic cancer pain, oftenin combination with non-steroid anti-inflammatory drugs (NSAIDs), aswell as acute pain (e.g. during recovery from surgery and breakthroughpain). Further, their use is increasing in the management of chronic,non-malignant pain.

Optimal management of chronic pain requires around-the-clock coverage.In this respect, opioid-requiring cancer patients are usually givenslow-release opioids (slow-release morphine, oxycodone or ketobemidone,or transdermal fentanyl or buprenorphine). Pharmaceutical formulationsthat are capable of providing a sustained release of active ingredientsallow the patient to obtain this baseline analgesia with a minimalnumber of doses per day. This in turn improves patient compliance andminimizes interference with the individual's lifestyle and thereforequality of life.

Transdermal fentanyl drug delivery systems comprise patches (e.g.DURAGESIC®) that are applied to the skin to deliver that potent opioidanalgesic, which is slowly absorbed through the skin into the systemiccirculation. Pain may be relieved for up to 3 days from a single patchapplication. Transdermal buprenorphine patches (e.g. BUTRANS®) relievepain for up to 7 days after a single patch administration.

In the design of sustained release formulations with extremely potentdrugs, such as opioids, the risk for “dose dumping” has to be eliminatedin view of the risk of severe and, on occasions, lethal side effects.Secondly, in some instances, patients may misuse their opioidmedication, e.g. by willfully (and sometimes unintentionally) tamperingwith an extended release formulation in order to get more immediateabsorption of opioid and a more rapid pain relieving effect. Thirdly, aperennial problem with potent opioid analgesics such as fentanyl is oneof abuse by drug addicts. Addicts often apply innovative techniques intheir abuse of pharmaceutical formulations, for example by way of one ormore of the following processes:

-   (a) extracting a large quantity of active ingredient from that    formulation using an appropriate eluent, such as an acid and/or    alcohol, to form a solution, which is then injected intravenously.    With most commercially-available pharmaceutical formulations, this    can be done relatively easily, which renders them unsafe or    “abusable”;-   (b) heating (and then smoking);-   (c) crushing of tablet (and then snorting); and/or-   (d) in the case of a patch, making a tea (and then drinking).

Thus, there is a clear unmet clinical need for an effectivepharmaceutical formulation that is capable of treating e.g. severe painvia a sustained release of active ingredients (such as opioidanalgesics), whilst at the same time minimising the possibility of dosedumping, misuse by opioid treated patients and/or abuse by addicts.

One solution to these problems that has been suggested is theincorporation of the active substance into a polymer matrix (see e.g.US2003/0118641 and US2005/0163856), which allows for the slow release ofthe active substance. However, this solution is not adequate as the drugabuser could either liberate the active substance from the polymermatrix by co-mixing with a solvent (either prior to ingestion, or thesolvent may be co-ingested with the polymer matrix/active substance) orby crushing the polymer matrix.

Ceramics are becoming increasingly useful to the medical world, in viewof the fact they are durable and stable enough to withstand thecorrosive effect of body fluids.

For example, surgeons use bioceramic materials for repair andreplacement of human hips, knees, and other body parts. Ceramics alsoare being used to replace diseased heart valves. When used in the humanbody as implants or even as coatings to metal replacements, ceramicmaterials can stimulate bone growth, promote tissue formation andprovide protection from the immune system. Dental applications includethe use of ceramics for tooth replacement implants and braces.

Ceramics are also known to be of potential use as fillers or carriers incontrolled-release pharmaceutical formulations. See, for example, EP 947489 A, U.S. Pat. No. 5,318,779, WO 2008/118096, Lasserre and Bajpai,Critical Reviews in Therapeutic Drug Carrier Systems, 15, 1 (1998),Byrne and Deasy, Journal of Microencapsulation, 22, 423 (2005) and Levisand Deasy, Int. J. Pharm., 253, 145 (2003).

In particular, Rimoli et al, J. Biomed. Mater. Res., 87A, 156 (2008), USpatent application 2006/0165787 and international patent applications WO2006/096544, WO 2006/017336 and WO 2008/142572 all disclose variousceramic substances for controlled release of active ingredients, withthe latter two documents being directed in whole or in part to opioidanalgesics, with the abuse-resistance being imparted by the ceramicstructures' mechanical strength.

Methods employed in these documents typically involve the incorporationof active ingredients into pre-formed porous ceramic materialscomprising e.g. porous halloysite, kaolin, titanium oxide, zirconiumoxide, scandium oxide, cerium oxide and yttrium oxide. In this respect,loading of active ingredient typically comprises soaking,extrusion-spheronization and/or cryopelletization. It is known to bedifficult to infuse drug into a pre-formed porous ceramic structure.Indeed, in the case of opioids, it is considered that such activeingredient-incorporation methodology will not enable the loading ofsufficient active ingredient to provide appropriate doses for effectivetherapeutic pain management, over a prolonged time, given that infusionof active ingredient into preformed pores is a difficult thing to do.

In WO 2008/142572, drugs are incorporated during the formation of aceramic carrier using chemically bonded ceramics, such as calciumaluminate or calcium silicate. Although this leads to a higher amount ofdrug incorporation than is typically the case for preformed ceramicmaterials, the mechanical strength and the chemical stability of theceramic structures described in WO 2008/142572 is, relatively speaking,limited, especially in acidic conditions. See also Forsgren et al, J.Pharm. Sci., 99, 219 (2010) and Jämstorp et al, J. Control. Release(2010) in press.

A composite material having a beneficial agent associated with at leasta portion of a high surface area component so as to increase thebioavailability and/or activity of the beneficial agent is disclosed inWO 02/13787. The high surface area component may be formed from amaterial having a hardness that is greater than the hardness of thebeneficial agent, and may be formed from metal oxides, metal nitrides,metal carbides, metal phosphates, carbonaceous materials, ceramicmaterials and mixtures thereof. The beneficial agent may be associatedwith the high surface area component by means of spraying, brushing,rolling, dip coating, powder coating, misting and/or chemical vapourdeposition.

Various methods of enhancing drug delivery by transdermal administrationare described by Banga in Expert Opin. Drug Deliv., 6, 343 (2009),including direct coating onto microneedles and administration via hollowmicroneedles. See also international patent application WO 03/090729 andWO 2009/113856, U.S. Pat. No. 6,334,856 and US patent application No. US2009/0200262.

An interface for a transdermal drug administration device is disclosedin US 2007/0123837. The interface may be provided in the form of a flatplate including two-dimensionally arranged projections, capable ofpiercing the skin, and a plurality of openings, capable of delivering adrug, respectively arranged in correspondence with the projections. Theprojections may be conical or pyramidal in shape and the flat plate andprojections may be formed from a metal, an alloy or a ceramic. In use,in a transdermal drug administration device for example, a drug inliquid form may be held in a drug-containing layer above the flat plate.When the flat plate is pressed against the skin, the plurality ofprojections pierce the skin and the drug is transferred from thedrug-containing layer, via the plurality of openings provided incorrespondence with the projections, through the holes formed in theskin.

A device for delivering bioactive agents through the skin is alsodisclosed in WO 03/092785. The device includes a plurality ofskin-piercing members and a porous calcium phosphate coating adapted asa carrier and provided on at least part of the skin-piercing members.The coating includes at least one bioactive agent and the skin-piercingmembers may be formed from metals, ceramics, plastics, semiconductors orcomposite materials.

Each of these documents refers to the possibility of loading and/orcombining an active ingredient with a pre-formed delivery device orother carrier, either by means of a separate drug-containing layerprovided in combination with the device or a coating applied to thedevice.

Disclosure of the Invention

According to the invention there is provided a transdermal drugadministration device comprising a drug delivery element defining acontact surface for location, in use, against a patient's skin, the drugdelivery element including a sustained-release pharmaceuticalcomposition comprising an active pharmaceutical ingredient co-formedlyinterspersed (dispersed) within pores of a solid, continuous networkcomprising a carrier material for the active pharmaceutical ingredientand possessing a high mechanical strength.

The term “sustained-release” is employed herein synonymously with theterm “controlled-release”, and will be understood by the skilled personto include compositions that provide, and/or are adapted to provide, fora “sustained”, a “prolonged” and/or an “extended” release of drug (inwhich drug is released at a sufficiently retarded rate to produce atherapeutic response over a required period of time).

We have advantageously found that the compositions used in the inventionprovide for release of active ingredient that is substantially uniformand/or nearly constant over an extended period of time. In oneembodiment, a nearly constant rate of release can vary over a doseinterval from about 30 minutes (e.g. about 6 to about 12 hours) to about(e.g. about 7, for example about 5, such as about 3) days. Constantrelease may further be defined as a composition being capable ofmaintaining a steady state concentration in a body fluid not deviatingmore than about 20% (e.g. about 10%) from the mean value during the doseinterval.

The network of the sustained release pharmaceutical composition mayeither be formed directly from a material that inherently possesses ahigh mechanical strength or may be formed as a consequence of a chemicalreaction between one or more precursor substances or materials, soforming the three-dimensional network in situ. In this respect, thenetwork may be designed to be inert in the following ways:

-   (a) general physico-chemical stability under normal storage    conditions, including temperatures of between about minus 80 and    about plus 50° C. (preferably between about 0 and about 40° C. and    more preferably room temperatures, such as about 15 to about 30°    C.), pressures of between about 0.1 and about 2 bars (preferably at    atmospheric pressure), relative humidities of between about 5 and    about 95% (preferably about 10 to about 75%), and/or exposure to    about 460 lux of UV/visible light, for prolonged periods (i.e.    greater than or equal to six months). Under such conditions, carrier    material networks as described herein may be found to be less than    about 5%, such as less than about 1% chemically degraded/decomposed,    as above;-   (b) particularly importantly when the active ingredient that is    employed is an opioid analgesic, general physico-chemical stability    under acidic, alkaline and/or alcoholic (e.g. ethanolic) conditions    at room temperature and/or under at elevated temperatures (e.g. up    to about 200° C.), which may result in less than about 15%    degradation, so avoiding the possibility of deliberate ex vivo    extraction of drug for intended abuse (e.g. by acid or alcohol    extraction, followed by injection, or heating a composition of the    invention and then an opioid addict inhaling the vapour or smoke    that is given off); and-   (c) again, particularly importantly when the active ingredient that    is employed is an opioid analgesic, general physical stability, for    example with a high mechanical impact strength, so reducing the    possibility of mechanical grinding or milling with a view to    extraction of active ingredient as defined in (b) above, or by an    opioid addict sniffing a resultant powder directly.

With reference to (c) above, it is preferred in this respect that thenetwork exhibits a compressive strength of greater than about 1 MPa,such as greater than about 5 MPa, e.g. about 10 MPa on micro- andnano-structure level, which is high enough to withstand breakdown of thematerial at the microstructure level, i.e. of less than about 200 μm.

In this respect, by network of “high mechanical strength” we alsoinclude that the structure of that network maintains its overallintegrity (e.g. shape, size, porosity, etc) when a force of about 1kg-force/cm² (9 newtons/cm²), such as about 5 kg-force/cm² (45newtons/cm²), such as about 7.5 kg-force/cm², e.g. about 10.0kg-force/cm², preferably about 15 kg-force/cm², more preferably about 20kg-force/cm², for example about 50 kg-force/cm², especially about 100kg-force/cm² or even about 125 kg-force/cm² (1125 newtons/cm²) isapplied using routine mechanical strength testing techniques known tothe skilled person (for example using a so-called “compression test” or“diametral compression test”, employing a suitable instrument, such asthat produced by Instron (the “Instron Test”, in which a specimen iscompressed, deformation at various loads is recorded, compressive stressand strain are calculated and plotted as a stress-strain diagram whichis used to determine elastic limit, proportional limit, yield point,yield strength and (for some materials) compressive strength)). When thestructure of the network is particulate, at least about 40% (e.g. atleast about 50%, such as at least about 60% preferably, at least about75%, and more preferably at least about 90%) of the particles (whetherprimary or secondary particles) maintain their integrity under theseconditions.

The carrier material that forms the solid, continuous network of thecomposition is preferably inorganic, but may also comprise an inertplastics or polymeric material, such as a polyacrylate or a copolymerthereof, a polyethylene glycol, a polyethylene oxide, a polyethylene, apolypropylene, a polyvinyl chlorides, a polycarbonate, a polystyrene, apolymethylmethacrylate, and the like.

In certain embodiments of the invention, the carrier material may bebased on one or more ceramic materials.

The term “ceramic” will be understood to include compounds formedbetween metallic and nonmetallic elements, frequently oxides, nitridesand carbides that are formed and/or processable by some form of curingprocess, which often includes the action of heat. In this respect, claymaterials, cement and glasses are included within the definition ofceramics (Callister, “Material Science and Engineering, An Introduction”John Wiley & Sons, 7^(th) edition (2007)).

It is preferred that the ceramic material that is employed is based uponan aluminate, such as a calcium aluminate or, more preferably, asilicate such as an aluminium (alumino) silicate. However, it may alsobe an oxide and/or a double oxide, and/or a nitride and/or a carbide ofany of the elements silicon, aluminium, carbon, boron, titanium,zirconium, tantalum, scandium, cerium, yttrium or combinations thereof.

Preferred materials include aluminium silicate and/or aluminium silicatehydrate (crystalline or amorphous). Non-limiting examples includekaolin, dickite, halloysite, nacrite, ceolite, illite or combinationsthereof, preferably halloysite. The grain size of the ceramic material(e.g. aluminium silicate) may be below about 500 μm, preferably belowabout 100 μm, and particularly below about 20 μm, as measured by laserdiffraction in the volume average mode (e.g. Malvern master size). Thegrains may be of any shape (e.g. spherical, rounded, needle, plates,etc.).

Ceramics may comprise chemically bonded ceramics (non-hydrated, partlyhydrated or fully hydrated ceramics, or combinations thereof).Non-limiting examples of chemically bonded ceramics systems includecalcium phosphate, calcium sulphates, calcium carbonates, calciumsilicates and calcium aluminates. Preferred chemical compositionsinclude those based on chemically bonded ceramics, which followinghydration of one or more appropriate precursor substances consume acontrolled amount of water to form a network of high mechanicalstrength. The preferred systems available are those based on aluminatesand silicates, both of which consume a great amount of water. Phasessuch CA2, CA, CA3 and C12A7, and C2S and C3S in crystalline or amorphousstate (C=CaO, A=Al₂O₃, SiO₂=S, according to common cement terminology)may be used, which are readily available. The calcium aluminate and/orcalcium silicate phases may be used as separate phase or as mixtures ofphases. The above-mentioned phases, all in non-hydrated form, act as thebinder phase (the cement) in the carrier material when hydrated.

The mean grain size of any ceramic precursor powder particles may bebelow about 100 μm, preferably between about 1 μm and about 20 μm. Thisis to enhance hydration. Such precursor material may be transformed intoa nano-size microstructure during hydration. This reaction involvesdissolution of the precursor material and repeated subsequentprecipitation of nano-size hydrates in the water (solution) and uponremaining non-hydrated precursor material. This reaction favourablycontinues until precursor materials have been transformed and/or until apre-selected porosity determined by partial hydration using the time andtemperature, as well as the H₂O in liquid and/or humidity, is measured.

In other (e.g. preferred) embodiments of the invention, the carriermaterial of the network of the composition may be based on one or moregeopolymer materials.

The term “geopolymer” will be understood by those skilled in the art toinclude or mean any material selected from the class of synthetic ornatural aluminosilicate materials which may be formed by reaction of analuminosilicate precursor substance (preferably in the form of a powder)with an aqueous alkaline liquid (e.g. solution), preferably in thepresence of a source of silica.

The term “source of silica” will be understood to include any form of asilicon oxide, such as SiO₂, including a silicate. The skilled personwill appreciate that silica may be manufactured in several forms,including glass, crystal, gel, aerogel, fumed silica (or pyrogenicsilica) and colloidal silica (e.g. Aerosil).

Suitable aluminosilicate precursor substances are typically (but notnecessarily) crystalline in their nature include kaolin, dickite,halloysite, nacrite, zeolites, illite, preferably dehydroxylatedzeolite, halloysite or kaolin and, more preferably, metakaolin (i.e.dehydroxylated kaolin). Dehydroxylation (of e.g. kaolin) is preferablyperformed by calcining (i.e. heating) of hydroxylated aluminosilicate attemperatures above 400° C. For example, metakaolin may be prepared asdescribed by Stevenson and Sagoe-Crentsil in J. Mater. Sci., 40, 2023(2005) and Zoulgami et al in Eur. Phys J. AP, 19, 173 (2002), and/or asdescribed hereinafter. Dehydroxylated aluminosilicate may also bemanufactured by condensation of a source of silica and a vapourcomprising a source of alumina (e.g. Al₂O₃).

Precursor substances may also be manufactured using sol-gel methods,typically leading to nanometer sized amorphous powder (or partlycrystalline) precursors of aluminosilicate, as described in Zheng et alin J. Materials Science, 44, 3991-3996 (2009). This results in a finermicrostructure of the hardened material. (Such as sol-gel route may alsobe used in the manufacture of precursor substances for the chemicallybonded ceramic materials hereinbefore described.)

If provided in the form of a powder, the mean grain size of thealuminosilicate precursor particles are below about 500 μm, preferablybelow about 100 μm, more preferred below about 30 μm.

In the formation of geopolymer materials, such precursor substances maybe dissolved in an aqueous alkaline solution, for example with a pHvalue of at least about 12, such as at least about 13. Suitable sourcesof hydroxide ions include strong inorganic bases, such as alkali oralkaline earth metal (e.g. Ba, Mg or, more preferably, Ca or, especiallyNa or K, or combinations thereof) hydroxides (e.g. sodium hydroxide).The molar ratio of metal cation to water can vary between about 1:100and about 10:1, preferably between about 1:20 and about 1:2.

A source of silica (e.g. a silicate, such as SiO₂) is preferably addedto the reaction mixture by some means. For example, the aqueous alkalineliquid may comprise SiO₂, forming what is often referred to aswaterglass, i.e. a sodium silicate solution. In such instances, theamount of SiO₂ to water in the liquid is preferably up to about 2:1,more preferably up to about 1:1, and most preferably up to about 1:2.The aqueous liquid may also optionally contain sodium aluminate.

Silicate (and/or alumina) may alternatively be added to the optionallypowdered aluminosilicate precursor, preferably as fume silica(microsilica; AEROSIL® silica). The amount that may be added ispreferably up to about 30 wt %, more preferably up to about 5 wt. % ofthe aluminosilicate precursor.

The presence of free hydroxide ions in this intermediate alkalinemixture, causes aluminium and silicon atoms from the source material(s)to be dissolved. The geopolymer materials may then be formed by allowingthe resultant mixture to set (cure or harden), during which process thealuminium and silicon atoms from the source materials reorientate toform a hard (and at least largely) amorphous geopolymeric material.Curing may be performed at room temperature, at elevated temperature orat reduced temperature, for example at around or just above ambienttemperature (e.g. between about 20° C. and about 90° C., such as around40° C.). The hardening may also be performed in any atmosphere, humidityor pressure (e.g. under vacuum or otherwise). The resultant inorganicpolymer network is in general a highly-coordinated 3-dimensionalaluminosilicate gel, with the negative charges on tetrahedral Al³⁺ sitescharge-balanced by alkali metal cations.

In this respect, a geopolymer-based carrier material may be formed bymixing a powder comprising the aluminosilicate precursor and an aqueousliquid (e.g. solution) comprising water, a source of hydroxide ions asdescribed hereinbefore and the source of silica (e.g. silicate), to forma paste. The ratio of the liquid to the powder is preferably betweenabout 0.2 and about 20 (w/w), more preferably between about 0.3 andabout 10 (w/w). Calcium silicate and calcium aluminate may also be addedto the aluminosilicate precursor component.

For the avoidance of doubt, whatever the network of carrier materialthat forms part of the sustained release pharmaceutical compositioncomprises, or is composed of, it is necessary to provide the activepharmaceutical ingredient together with either:

-   (a) particulate, pre-formed ceramic, geopolymeric or polymeric    material; or-   (b) some sort of “precursor” to the ceramic, geopolymeric or    polymeric material,    for example in the form of a paste, and then perform some sort of    appropriate (e.g. curing or bonding) process, which comprises    either:-   (i) bonding together (physically or chemically) the particles (a);    or-   (ii) in the case of (b), a chemical reaction,    to form, in both cases, the solid, continuous, three-dimensional    network with a high mechanical strength.

In accordance with the invention, the active pharmaceutical ingredientis co-formedly interspersed in pores within the carrier materialnetwork. This means that, whatever process is employed to form thesolid, continuous, three-dimensional network with high mechanicalstrength, it must also necessarily form pores within which activepharmaceutical ingredient is interspersed.

The active ingredient may thus be mixed with the carrier material (e.g.ceramic or geopolymer) or precursor(s) thereto, by way of a variety oftechniques, such as introduction by way of a sol-gel process, as asolution, or as a slurry, a paste or a putty of, for example, particles,granules or pellets of carrier material or precursor(s) thereto, in thepresence of an appropriate liquid (e.g. an aqueous or organic solvent).This is followed by some sort of “curing” process to form the sustainedrelease composition, which comprises said pores, within which the activeingredient resides.

Such pores are themselves a three-dimensional network of channels orvoids within the solid network, containing (e.g. particles) of activeingredient, and are thus to be distinguished from pre- or post-formedchannels (in, for example, microneedles) through which drug isadministered to or through the skin in the form of a pharmaceuticalcompositions (e.g. a solution).

Such pores may thus be essentially “secondary pores” formed by chemicalinteractions (e.g. “bonding”) between the surfaces of primary particlesof (e.g. inorganic) materials of high mechanical strength (which may beporous in their own right (i.e. comprise “primary” pores), such asceramics or geopolymers. Such pores may, for example, result fromexposure of such materials to one or more chemical reagents that cause aphysical and/or chemical transformation (such as a partial dissolution)at, and subsequent physical and/or chemical bonding together of, thosesurfaces (which may in itself result as a consequence of some otherphysico-chemical process such as drying, curing, etc.), giving rise tosaid pores/voids.

In such instances, such chemical reagents may be mixed together withactive pharmaceutical ingredient during preparation of the sustainedrelease composition. However, such secondary pores are not necessarilyformed in this way, and bonding together of primary particles of carriermaterials may also be physical and/or mechanical.

Thus, in such embodiments of the invention, a sustained-releasepharmaceutical composition is provided, comprising a solid, continuousthree-dimensional network comprising particles of a (preferablyinorganic) carrier material, which particles are bonded together to formsecondary pores or voids, and an active ingredient interspersed withinsaid voids.

Alternatively, if the network is formed by way of a chemical reaction(e.g. polymerisation, or as described hereinbefore for geopolymers),active ingredient may be co-mixed with a precursor mixture comprisingrelevant reactants and thereafter located within pores or voids that areformed during formation of the three-dimensional carrier materialnetwork itself. Although it is not essential in all cases, it may bethat, in some cases, it is necessary to include a porogenic material aspart of the reaction mixture in order to assist in the formation ofpores within the final carrier material network, within which activepharmaceutical ingredient is co-formedly interspersed. Porogenicmaterials include, for example, oils, liquids (e.g. water), sugars,mannitol etc.

The composition may further include a film forming agent co-formedlyinterspersed within the pores of the network.

When used herein, the term “film-forming agent” refers to a substancethat is capable of forming a film over (or within), or coating over,another substance or surface (which may be in particulate form).

The use of a film forming agent improves the tamper resistance of thetransdermal drug administration device and may also furtheradvantageously increase the mechanical strength of the composition.These features, together with the controlled-release properties of thecomposition, provide advantages associated with the prevention of dosedumping and potential misuse or drug abuse by ex vivo extraction of theactive pharmaceutical ingredient, when the latter comprises an opioidanalgesic or other compound with a risk of misuse/abuse.

It is preferred that any such film-forming agent is a material that iscapable of providing a sustained-release, delayed-release or,preferably, enteric-release coating (i.e. an enteric coating material).Substances that are capable of providing an enteric coating are thusthose that may be employed in peroral pharmaceutical formulations as abarrier to prevent or minimise release of active ingredient prior tosuch formulations reaching the small intestine.

In this respect, it is preferred that the film-forming agent is apolymer. Examples of polymers that may be employed as film-formingagents include, without limitation: alkylcellulose polymers (e.g.ethylcellulose polymers), and acrylic polymers (e.g. acrylic acid andmethacrylic acid copolymers, methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, methyl methacrylate, copolymers, methacrylic acidcopolymers, methyl methacrylate copolymers, methyl methacrylatecopolymers, methacrylate copolymers, methacrylic acid copolymer,aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methylmethacrylate copolymers, poly(acrylic acid), poly(methacrylic acid,methacrylic acid alkylamid copolymer, poly(methyl methacryate),poly(methacrylic acid) (anhydride), methyl methacrylate,polymethacrylate, methyl methacrylate copolymer, poly(methylmethacrylate), poly(methyl methacrylate) copolymer, polyacryamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers). The polymer may also be a mixture ofpolymers. Typically, the molecular weight (weight average and/or numberaverage) of the polymer is 1,000 to 10,000,000, 10,000 to 1,000,000,preferably 50,000 to 500,000 g/mol, as measured by gel permeationchromatography.

Preferred polymers include the alkyl cellulose polymers and acrylicpolymers described herein.

The film-forming agent may comprise a polymer that exhibits anioniccharacter and/or is weakly acidic (for example that have or provide a pHof less than 7, and preferably less than 5, in an aqueous medium).

Most preferred polymers includes those derived from methacrylic acid andethyl acrylate (preferably in a 1:1 ratio), or neutral methacrylicpolymers with acid or alkaline groups, including those marketed underthe trademarks Kollicoat® and Eudragit®. For example, Kollicoat® MAE 30DP (BASF) is a copolymer of methacrylic acid/ethyl acrylate (1:1), andis available as an aqueous dispersion or powder. Other polymers that maybe mentioned include Eudragit® L100-55.

In embodiments in which a film-forming agent is included in thecomposition, the admixing of active ingredient and film-forming agentmay take place prior to or during interspersion within the network ofcarrier material, such that the majority (i.e. greater than about 50%,such as greater than about 75%) of those components are added to thecarrier material or precursor(s) thereto at essentially the same time,and not separately, such that there is substantially uniformblending/inter-mixing of the components as defined above. Mostpreferably, there is a substantially uniform content (i.e. variations ofno more than about ±50%, such as about ±40%, preferably about ±30%, morepreferably about ±20% and particularly about ±10%) of the activeingredient throughout the film-forming agent, and/or there is noparticular location within the film-forming agent where there is asubstantially greater concentration of the active ingredient to providea homogeneous distribution.

The composition may further comprise one or more commonly-employedpharmaceutical excipients. Suitable excipients include inactivesubstances that are typically used as a carrier for the activepharmaceutical ingredients in medications. Suitable excipients alsoinclude those that are employed in the pharmaceutical arts to bulk updrug delivery systems that employ very potent active pharmaceuticalingredients, to allow for convenient and accurate dosing. Alternatively,excipients may also be employed to aid in the handling of the activepharmaceutical ingredient concerned.

In this respect, pharmaceutically-acceptable excipients include fillerparticles, by which we include particles that do not take part in anychemical reaction during which a composition is formed. Such fillerparticles may be added as ballast and/or may provide the compositionwith functionality.

The composition may also optionally contain bulking agents, porogens, pHmodifiers, dispersion agents or gelating agents to control the rheologyor the amount of liquid in the geopolymer. The total amount of suchexcipients is limited to about 20 wt % of the total weight of theprecursor and liquid combined. Non-limiting examples of such excipientsinclude polycarboxylic acids, cellulose, polyvinylalcohol,polyvinylpyrrolidone, starch, nitrilotriacetic acid (NTA), polyacrylicacids, PEG, glycerol, sorbitol, mannitol and combinations thereof.

Additional pharmaceutically-acceptable excipients include carbohydratesand inorganic salts such as sodium chloride, calcium phosphates, calciumcarbonate, calcium silicate and calcium aluminate. In the case ofnetworks based on geopolymers, such additional materials are preferablyadded to the aluminosilicate precursor component.

As defined herein, the drug delivery element defines a contact surfacefor location, in use, against a patient's skin and includes thesustained-release pharmaceutical composition comprising the carriermaterial network and active pharmaceutical ingredient. Accordingly, itis not essential that the sustained-release pharmaceutical compositionis placed in direct contact with the skin. Indeed, the composition maybe coated with a coating material (e.g. a thin, porous film orhydrophilic or hydrophobic chemical substances, such as surface activemolecules, e.g. silicones or fluoroalkyl materials).

The drug delivery element of the drug delivery device according to theinvention may take several forms, provided that it defines a contactsurface for location, in use, against a patient's skin.

For example, the composition may be incorporated into the drug deliveryelement of the transdermal drug administration device in the form ofpellets or particles of the composition. In such embodiments, thepellets may be embedded in any conventional transdermal patch system,such as a membrane or a matrix to form the drug delivery element. Aconventional transdermal patch system may comprise for example of abacking layer, a drug matrix (e.g. a pellets or particles embedded in ahydrogel, a fat or any suitable polymer) or a drug reservoir (drug inthe form of solution or suspension), a membrane (optional) and anadhesive.

The term “matrix” will be understood to include any material wherepellets or particles of the composition are formed or embedded. The term“hydrogel” will be understood to include a highly absorbent natural orsynthetic polymer, such as HPMC or PVA.

The embedding of pellets or particles of the composition in, forexample, a hydrogel, such as a cryogel, creates a pre-saturated gel thatis able to administer the active pharmaceutical ingredient co-formedlyinterspersed within such pellets or particles when the contact surfaceof the drug delivery element is located, in use, against a patient'sskin.

Granules or pellets of the composition may be formed by mixing togetherthe carrier material (e.g. ceramic or geopolymeric material), orprecursor(s) thereto, and the active substance, optionally adding afilm-forming agent along with, or in, a liquid, such as an aqueoussolvent (e.g. water), so providing a wet granulate. Wet granulationtechniques are well known to those skilled in the art and include anytechnique involving the massing of a mix of dry primary powder particlesusing a granulating fluid, which fluid comprises a volatile, inertsolvent, such as water, optionally in the presence of a pelletisationaid material. The product so obtained may further be adapted by:

-   (I) spheronisation (forcing a wet mass through a sieve to produce    pellets);-   (II) drying; and/or-   (III) (if necessary) hardening by way of heat at temperatures of    20-90° C. for >1 hour, using routine techniques in all cases.

Alternatively, granules or pellets may be formed by forming a wet paste(rather than a granulate) as described above, and directly moulding thepaste into the desired shape. The paste is preferably moulded into apolymer mould or into polymer coated metal or ceramic mould (e.g. Tefloncoating). After moulding, the paste may be hardened (in a preferablywarm and moist environment) to the final desired shape.

If granules or pellets of geopolymer are to be employed, preformedgeopolymer may be reacted together further aluminosilicate precursor andaqueous alkaline liquid (e.g. solution), preferably in the presence of asource of silica (as hereinbefore described), also in the presence ofthe active ingredient and optionally the film-forming agent (or theactive ingredient optionally interspersed or dry-mixed with thefilm-forming agent) as hereinbefore described. Curing may thereafter beperformed by allowing the resultant mixture to harden into the requiredshape, i.e. granules or pellets.

Alternatively, pellets may be manufactured using an appropriateextrusion-spheronization technique. Here, the formed paste (powder andliquid mixture) may be extruded through an orifice. The size of theorifice may be from about 10 μm up to about 30 mm, preferably from about100 μm to about 1 mm. The formed extrudate may then be placed in aspheronizer, which is typically a vertical hollow cylinder with ahorizontal rotating disk located inside. When the disk is spun, theextrudate is broken into uniform lengths and gradually formed intospherical pellets, which may then be left to harden as describedhereinbefore.

In embodiments in which the drug delivery element includes pellets ofthe composition, suitable mean pellet/granule sizes are in the range ofabout 0.05 mm to about 3.0 mm (e.g. about 2.0 mm, such as about 1.7 mm),and preferably about 0.1 mm (e.g. about 0.2 mm) to about 1.6 mm (e.g.about 1.5 mm), such as about 1.0 mm.

Compositions in the form of small particles of a mean size range ofabout 0.0001 mm to about 5 mm (e.g. about 0.5 mm), preferably about0.001 mm to about 0.5 mm (e.g. about 0.05 mm), may also be attached to,or embedded within, an adhesive surface, with or without a backinglayer, which is then placed in contact with the skin. In such systems,all, some or none of the small particles may thereafter be in directcontact with the skin upon application. Such small particles may be madeby forming a material network with high mechanical strength as describedhereinbefore and then crushing (e.g. using a jaw crusher) and/or millingto the desired mean grain size (e.g. using a planetary mill). The formedgrains may be essentially angular (i.e. irregular shapes that areessentially not spherical/round).

In the aforementioned embodiments, the composition may further include apellitisation aid material. A pelletisation aid material may be definedas a material that is capable of controlling the distribution ofgranulating liquid through the wet powder mass during pelletisation andto modify the rheological properties in the mixture. Suitablepelletisation aid materials include hydroxypropylmethylcellulose (HPMC),hydroxyethylcellulose (HEC) and, preferably, microcrystalline cellulose.If present, the pelletisation aid material is preferably employed in anamount of between 0.5 and 50% by weight based upon the total weight ofthe tablet formulation. A preferred range is from 1 to 20%, such as fromabout 2.0 to about 12% (e.g. about 10%) by weight.

In other embodiments, the composition may be moulded during formationinto one or more homogeneous layers (e.g. in the form of one or moreuniform layers, elements, plates or disks) that may be flat and/or thindefining a drug delivery element in which the active pharmaceuticalingredient is co-formedly dispersed within pores in a solid network ofcarrier material. Typical dimensions for a single element to be appliedto the skin may be in the range of between about 2 cm (e.g. about 5 cm)and about 10 cm by about 2 cm (e.g. about 5 cm) and about 10 cm.Preferred size ranges for single elements are about 5 cm by about 5 cm,such as about 2 cm by about 2 cm, with a thickness of up to about 1 cm,preferably up to about 0.5 cm, such as up to about 0.02 cm. Any of theaforementioned dimensions may be used in combination. Furthermore,multiple elements of the same or different dimensions (e.g. smallerelements of about 1 mm by about 1 mm) may be applied to the skin at thesame time to make a “mosaic” pattern of elements.

In such embodiments, the homogeneous layer may be moulded to define asubstantially flat contact surface for location, in use, against apatient's skin (in either direct or indirect contact as describedhereinbefore).

The term “substantially flat contact surface” will be understood toinclude a flat contact surface that excludes any pre-formed protrusionsand includes only undulations or variations resulting from the mouldingprocess.

In other such embodiments, the homogeneous layer may be moulded todefine a contact surface including an array of microscopic protrusionsfor location, in use, against a patient's skin.

The term “microscopic protrusions” may be provided in the form of anyshape that has a base and one or more sloping sides to define (e.g. inthe case of more than one side to meet generally centrally at) an apex(i.e. point or ridge, which may be rounded), for example pyramidalprotrusions or conical protrusions. Such protrusions may be of about 4μm to about 700 μm in height and have a width at their lower bases ofabout 0.1 μm to about 200 μm.

The provision of microscopic protrusions increases the surface area ofthe contact surface of the drug element available for location against apatient's skin and thereby increases the size (i.e. the contact surfacearea) of the drug reservoir available for administration via thepatient's skin. This improves the transport of the active pharmaceuticalingredient from the drug delivery element via pores in the skin barrierso as to facilitate absorption of the active pharmaceutical ingredientthrough the skin barrier.

It thus improves the efficiency of the drug delivery element inadministering the active pharmaceutical ingredient. The use of suchmicroscopic protrusions is advantageous in the treatment of e.g. chronicdisorders in which the ongoing administration of an activepharmaceutical ingredient is required.

Other shapes may be moulded into the contact surface(s) of the drugdelivery element in order to increase hydrophobicity or hydrophilicityof at least part of the resultant surface (with or without theemployment of surface active molecules). The drug delivery element maythus make use of the so-called “lotus effect”, in which the contactangle of certain microscopic protrusion(s) at the surface is high enough(e.g. >90°) to be hydrophobic and/or low enough (e.g. <90°) to behydrophilic. The moulded structure may thus be designed so that thesurface of the drug delivery element is capable of channelling moisturefrom one part to another, for example any part of the drug deliveryelement where there are pores comprising active ingredient.

Combinations of the aforementioned microscopic protrusion patterns maybe employed in the drug delivery element.

In a further embodiment, the homogeneous layer may be moulded to definean array of micro-needles protruding from the contact surface of thedrug delivery element.

The term “micro-needles” will be understood to include sharp protrusionshaving a length of 4 μm to 700 μm and having a width at their lowerbases of 1 μm to 200 μm, which, on placement of a contact surfaceincluding an array of micro-needles against a patient's skin, createmicron-sized micropores or microchannels in the skin. This facilitatesmore rapid delivery of active pharmaceutical ingredients, and/or thedelivery of larger molecules such as peptides and proteins, for example,which cannot otherwise penetrate the skin barrier.

The size of the micro-needles moulded so as to protrude from the contactsurface of the drug delivery element may be varied depending on thenature of the active pharmaceutical ingredient interspersed in the drugdelivery element so as to alter the extent of penetration of the needlesinto the skin barrier.

The homogeneous layer may be moulded to define an array of solidmicro-needles, and may further be moulded to define an array of hollowmicro-needles. The use of hollow micro-needles allows the accuratedelivery of larger molecules of active pharmaceutical ingredient viaholes formed in the tips of the micro-needles directly into themicropores or microchannels formed in a patient's skin. Any such holesmay have a diameter of between 10 μm and 100 μm.

The use of micro-needles that penetrate a patient's skin is advantageousin the treatment of acute disorders in which a rapid onset of actionfrom an active pharmaceutical ingredient is required. The creation ofmicropores or microchannels in the patient's skin accelerates the rateat which drug molecules can be absorbed into the patient's bloodstreamwhen compared with the use of a flat contact surface or a contactsurface including a plurality of microscopic protrusions.

In embodiments in which the drug delivery element is provided in theform of a homogeneous layer of the composition, so as to define asubstantially flat contact surface or so as to define a contact surfaceincluding an array of microscopic protrusions or micro-needlesprotruding therefrom, the homogeneous layer may be formed by filling aproduction mould with the wet mass of active pharmaceutical ingredientand carrier material or precursor(s) thereto, and forming the curing orbonding step mentioned hereinbefore in situ.

The mould is chosen to define the desired geometry of the resultanthomogeneous layer and the wet mass is preferably chemically hardened(i.e. hardens or otherwise cures via chemical reactions) to form thepores in which the active pharmaceutical ingredient (and optionallyfilm-forming agent) is co-formedly dispersed.

Such moulded elements may be formed by mixing together the carriermaterial (e.g. ceramic or geopolymeric material), or precursor(s)thereto, and the active substance, optionally adding a film-formingagent along with, or in, a liquid, such as an aqueous solvent (e.g.water), so providing a wet paste, and directly moulding the paste intothe desired shape. The paste is preferably moulded into a polymer mouldor into polymer coated metal or ceramic mould (e.g. Teflon coating).After moulding the paste may be hardened (in a preferably warm and moistenvironment) to the final desired shape. For example, in the case ofgeopolymer-based carrier materials, aluminosilicate precursor may bereacted together with aqueous alkaline liquid (e.g. solution),preferably in the presence of a source of silica (as hereinbeforedescribed), also in the presence of the active ingredient (and/or otherexcipients, such as a film-forming agent) as hereinbefore described andcuring thereafter performed by allowing the resultant mixture to hardeninto the required homogeneous layer shape. Alternatively, preformedgeopolymer may be reacted together further aluminosilicate precursor andaqueous alkaline liquid (e.g. solution), in the presence of the activeingredient and optionally a source of silica and curing thereafterperformed as described above. In this respect, the mixture may betransferred into moulds and left to set as the homogeneous layer.

In such embodiments, the mould in which the homogeneous layer ofcomposition is formed may form a blister packaging for the drug deliveryelement, the bottom of the blister forming the negative mould for anymicroscopic protrusions or micro-needles formed so as to protrude fromthe contact surface.

Such moulds may be formed by etching (chemical or physical (e.g. by wayof a laser)) or known micromechanical techniques, such as softlithography. Soft lithography is the general name for a number ofdifferent nanofabrication techniques in which a master initially isproduced on a silicon wafer, for example UV-photolithography. Here, adevice layout is printed on a transparency or on a chrome mask, makingsome areas transparent and others oblique to UV-light. A silicon waferis then spin-coated with a photo-curable resist, which is exposed toUV-light through the mask. The wafer is then subjected to an etchingsolution that removes the uncured photoresist to make the master. Themaster is then used as a mould to cast a negative structure in anelastomer. This elastomer casting is either the end product, or it inturn is used as a mould to make another generation of castings withstructures similar to those of the silicon master (see, for example,Madou, Fundamentals of Microfabrication: The Science of Miniaturization,2^(nd) ed. (2002), Boca Raton: CRC Press. 723 and Weigl et al, AdvancedDrug Delivery Reviews (2003) 55, 349-377 for further information).

The active pharmaceutical ingredients employed in the compositionincluded in the drug delivery element preferably include substances fromvarious pharmacological classes, e.g. antibacterial agents,antihistamines and decongestants, anti-inflammatory agents,antiparasitics, antivirals, local anaesthetics, antifungals,amoebicidals or trichomonocidal agents, analgesics, antianxiety agents,anticlotting agents, antiarthritics, antiasthmatics, anticoagulants,anticonvulsants, antidepressants, antidiabetics, antiglaucoma agents,antimalarials, antimicrobials, antineoplastics, antiobesity agents,antipsychotics, antihypertensives, auto-immune disorder agents,anti-impotence agents, anti-Parkinsonism agents, anti-Alzheimer'sagents, antipyretics, anticholinergics, anti-ulcer agents,blood-glucose-lowering agents, bronchodilators, central nervous systemagents, cardiovascular agents, cognitive enhancers, contraceptives,cholesterol-reducing agents, agents that act against dyslipidermia,cytostatics, diuretics, germicidials, hormonal agents, anti-hormonicalagents, hypnotic agents, inotropics, muscle relaxants, musclecontractants, physic energizers, sedatives, sympathomimetics,vasodilators, vasocontrictors, tranquilizers, electrolyte supplements,vitamins, uricosurics, cardiac glycosides, membrane efflux inhibitors,membrane transport protein inhibitors, expectorants, purgatives,contrast materials, radiopharmaceuticals, imaging agents, peptides,enzymes, growth factors, vaccines, mineral trace elements.

The active pharmaceutical ingredients preferably include any that areopen to abuse potential, such as those that are useful in the treatmentof acute or chronic pain, attention deficit hyperactivity disorders(ADHD), anxiety and sleep disorders, as well as growth hormones (e.g.erythropoietin), anabolic steroids, etc. A full list of potentiallyabusable substances may be found easily by the skilled person, forexample see the active ingredients listed on the following weblink:http://www.deadiversion.usdoj.gov/schedules /alpha/alphabetical.htm.

Non-opioid drug substances that may be specifically mentioned includepsychostimulants, such as modafinil, amphetamine, dextroamphetamine,methamphetamine and hydroxyamphethamine and, more preferably,methylfenidate; benzodiazepines, such as bromazepam, camazepam,chlordiazepoxide, clotiazepam, cloxazepam, delorazepam, estazolam,fludiazepam, flurazepam, halazepam, haloxazepam, ketazolam,lormetazepam, medazepam, nimetazepam, nordiazepam, oxazolam, pinazepam,prazepam, temazepam, tetrazepam and, more preferably, alprazolam,clonazepam, diazepam, flunitrazepam, lorazepam, midazolam, nitrazepam,oxazepam and triazolam; and other, non-benzodiazepine sedatives (e.g.short-acting hypnotics), such as zaleplon, zolpidem, zopiclone andeszopiclone.

Preferred pharmaceutically-active ingredients that may be employed inthe composition include opioid analgesics. The term “opioid analgesic”will be understood by the skilled person to include any substance,whether naturally-occurring or synthetic, with opioid or morphine-likeproperties and/or which binds to opioid receptors, particularly thep-opioid receptor, having at least partial agonist activity, therebycapable of producing an analgesic effect. The problems of potentialformulation tampering and drug extraction by drug addicts areparticularly prominent with opioids.

Opioid analgesics that may be mentioned include opium derivatives andthe opiates, including the naturally-occurring phenanthrenes in opium(such as morphine, codeine, thebaine and Diels-Alder adducts thereof)and semisynthetic derivatives of the opium compounds (such asdiamorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone,etorphine, nicomorphine, hydrocodeine, dihydrocodeine, metopon,normorphine and N-(2-phenylethyl)normorphine). Other opioid analgesicsthat may be mentioned include fully synthetic compounds with opioid ormorphine-like properties, including morphinan derivatives (such asracemorphan, levorphanol, dextromethorphan, levallorphan, cyclorphan,butorphanol and nalbufine); benzomorphan derivatives (such ascyclazocine, pentazocine and phenazocine); phenylpiperidines (such aspethidine (meperidine), fentanyl, alfentanil, sufentanil, remifentanil,ketobemidone, carfentanyl, anileridine, piminodine, ethoheptazine,alphaprodine, betaprodine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP), diphenoxylate and loperamide), phenylheptamines or “open chain”compounds (such as methadone, isomethadone, propoxyphene andlevomethadyl acetate hydrochloride (LAAM)); diphenylpropylaminederivatives (such as dextromoramide, piritramide, bezitramide anddextropropoxyphene); mixed agonists/antagonists (such as buprenorphine,nalorphine and oxilorphan) and other opioids (such as tilidine, tramadoland dezocine). Further opioid analgesics that may be mentioned includeallylprodine, benzylmorphine, clonitazene, desomorphine, diampromide,dihydromorphine, dimenoxadol, dimepheptanol, dimethyfthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethylmethylthiambutene,ethylmorphine, etonitazene, hydroxypethidine, levophenacylmorphan,lofentanil, meptazinol, metazocine, myrophine, narceine, norpipanone,papvretum, phenadoxone, phenomorphan, phenoperidine and propiram.

More preferred opioid analgesics include buprenorphine, alfentanil,sufentanil, remifentanil and, particularly, fentanyl.

Active ingredients listed above may also be formulated in thecomposition in any specific combination.

In the case of drug delivery devices comprising opioid analgesics, inorder to further improve abuse-deterrent properties, an opioidantagonist with limited or no transdermal absorption may be included inthe composition together with the opioid. Any attempt to tamper with theformulation for subsequent injection, will also release the antagonistand therefore potentially prevent the desired abuse-generatedpharmacological effect. Examples of opioid antagonists and partialopioid antagonists include naloxone, naltrexone, nalorphine andcyclazocine.

Active pharmaceutical ingredients may further be employed in salt formor any other suitable form, such as e.g. a complex, solvate or prodrugthereof, or in any physical form such as, e.g., in an amorphous state,as crystalline or part-crystalline material, as co-crystals, or in apolymorphous form or, if relevant, in any stereoisomeric form includingany enantiomeric, diastereomeric or racemic form, or a combination ofany of the above.

Pharmaceutically-acceptable salts of active ingredients that may bementioned include acid addition salts and base addition salts. Suchsalts may be formed by conventional means, for example by reaction of afree acid or a free base form of an active ingredient with one or moreequivalents of an appropriate acid or base, optionally in a solvent, orin a medium in which the salt is insoluble, followed by removal of saidsolvent, or said medium, using standard techniques (e.g. in vacuo, byfreeze-drying or by filtration). Salts may also be prepared byexchanging a counter-ion of active ingredient in the form of a salt withanother counter-ion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable addition salts include thosederived from mineral acids, such as hydrochloric, hydrobromic,phosphoric, metaphosphoric, nitric and sulphuric acids; from organicacids, such as tartaric, acetic, citric, malic, lactic, fumaric,benzoic, glycolic, gluconic, succinic, arylsulphonic acids; and frommetals such as sodium, magnesium, or preferably, potassium and calcium.

The drug delivery element of the transdermal drug administration devicecontains a pharmacologically effective amount of the active ingredient.By “pharmacologically effective amount”, we refer to an amount of activeingredient, which is capable of conferring a desired therapeutic effecton a treated patient (which may be a human or animal (e.g. mammalian)patient), whether administered alone or in combination with anotheractive ingredient. Such an effect may be objective (i.e. measurable bysome test or marker) or subjective (i.e. the subject gives an indicationof, or feels, an effect).

Preferably the drug delivery element may be adapted (for example asdescribed herein) to provide a sufficient dose of drug over the dosinginterval to produce a desired therapeutic effect.

The amounts of active ingredients that may be employed in the drugdelivery element may thus be determined by the physician, or the skilledperson, in relation to what will be most suitable for an individualpatient. This is likely to vary with the type and severity of thecondition that is to be treated, as well as the age, weight, sex, renalfunction, hepatic function and response of the particular patient to betreated.

When the drug delivery element includes opioid analgesics, appropriatepharmacologically effective amounts of such opioid analgesic compoundsinclude those that are capable of producing (e.g. sustained) relief ofpain when administered.

Drug delivery elements including opioid analgesics are useful in thetreatment of pain, particularly severe and/or chronic pain. According toa further aspect of the invention there is provided a method oftreatment of pain which comprises locating a contact surface of such adrug delivery element of a transdermal drug administration deviceaccording to the invention against the skin of a patient suffering from,or susceptible to, such a condition.

For the avoidance of doubt, by “treatment” we include the therapeutic(including curative) treatment, as well as the symptomatic treatment,the prophylaxis, or the diagnosis, of the condition.

Transdermal drug administration devices of the invention possess theadvantage of the avoidance and/or reduction of the risk of either dosedumping (i.e. the involuntary release), or equally importantly thedeliberate ex vivo extraction, of the majority (e.g. greater than about50%, such as about 60%, for example about 70% and in particular about80%) of the dose of the active ingredient(s) that is initially withinthe composition included in the drug delivery element, within atimeframe that is likely to give rise to undesirable consequences, suchas adverse pharmacological effects, or the potential for abuse of thatactive ingredient (for example when such release is deliberatelyeffected ex vivo by an individual).

Transdermal drug administration devices of the invention have theadvantage that the composition included in the drug delivery elementprovides sustained release properties with minimal risk forsevere/lethal side effects (i.e. reduction of dose dumping and/or abusepotential when the active ingredient to be employed is abusable, such asan opioid, a benzodiazepine, etc.). The composition may provideprotection against intentional mechanical breakdown, e.g. by traditionalmethods such as crushing, pestle and mortar, hammering etc by having ahigh compressive strength level at the micro-level. This protection maybe provided by the composition as such, and especially when thosecompositions are employed in conjunction with a carrier or filler thatalso possesses high mechanical strength.

Transdermal drug administration devices of the invention may also havethe advantage that the composition included in the drug delivery elementmay be prepared using established pharmaceutical processing methods andmay employ materials that are approved for use in foods orpharmaceuticals or of like regulatory status.

Transdermal drug administration devices of the invention may also havethe advantage that the composition included in the drug delivery elementmay be more efficacious than, be less toxic than, be longer acting than,be more potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile than, and/orhave other useful pharmacological, physical, or chemical propertiesover, pharmaceutical compositions known in the prior art, whether foruse in the treatment of pain or otherwise.

Wherever the word “about” is employed herein in the context ofdimensions (e.g. values, temperatures, pressures (exerted forces),relative humidities, sizes and weights, particle or grain sizes, poresizes, timeframes etc.), amounts (e.g. relative amounts (e.g. numbers orpercentages) of particles, individual constituents in a composition or acomponent of a composition and absolute amounts, such as doses of activeingredients, numbers of particles, etc), deviations (from constants,degrees of degradation, etc) it will be appreciated that such variablesare approximate and as such may vary by ±10%, for example ±5% andpreferably ±2% (e.g. ±1%) from the numbers specified herein.

The invention is illustrated by the following examples in which:

FIGS. 1 and 2 show drug delivery elements of transdermal drug deliveryelements made from metakaolin and zolpidem tartrate, and employingsodium silicate solution and water as the granulation liquid. The scalein FIG. 1 is a centimetre scale.

FIGS. 3 and 4 shows the release profile of zolpidem tartrate inphosphate buffer (pH 6.8) from the drug delivery elements shown in FIGS.1 and 2.

EXAMPLE 1 Zolpidem-Containing Transdermal Drug Delivery Element

Drug delivery elements 10 of transdermal drug administration devices(not shown) are shown in FIGS. 1 and 2.

Each drug delivery element 10 is a homogeneous layer moulded to define acontact surface 12 including a plurality of microscopic projections 14.The projections 14 are pyramidal in shape, having a height of 4 μm and awidth at their base of 10 μm.

The drug delivery element 10 shown in FIGS. 1 and 2 was formed inaccordance with the following method.

Kaolin was heated at 800° C. for 2 hours in order to form metakaolin. 4g of the metakaolin was mixed with 0.12 g of zolpidem tartrate as theactive pharmaceutical ingredient, by hand, in a mortar. 5 g of sodiumsilicate solution and 1 g of water were added to the mixture so as toform a wet mass.

The wet mass was moulded in a plexiglass disc on the bottom of which apyramidal pattern had been produced using a soft lithography technique,so as to produce the pyramidal projections shown in FIG. 2. A chemicalreaction between the sodium silicate solution and the metakaolinresulted in hardening of the wet mass so as to form a solid, continuousnetwork of metakaolin, the network further defining a plurality of poresin which the zolpidem tartrate is dispersed.

The in vitro release profile of the active pharmaceutical ingredient,zolpidem tartrate, of the drug delivery element 10 was measured usingthe United States Pharmacopoeia <711> (USP) dissolution paddle method.The paddle rotation rate was 50 rpm and 200 mL of phosphate bufferhaving a pH of 6.8 was used. Samples were withdrawn after 1, 2, 3, 4, 6and 72 hours and the amount of active pharmaceutical ingredient wasdetermined uysing High Performance Liquid Chromatography (HPLC). Therelease profile obtained is shown in FIG. 3.

The release profile rate was also evaluated using a dish rag/cloth(wettex) method. In this evaluation, 400 μL of phosphate buffer wasplaced on a piece of wettex material measuring 3 cm×3 cm. A para filmand a metal plate were placed over the wettex material. The drug wasextracted from the wettex material after 6 and 24 hours and the amountof active pharmaceutical ingredient was determined uysing HighPerformance Liquid Chromatography (HPLC). The release profile obtainedis shown in FIG. 4.

On reviewing the release profiles shown in FIGS. 3 and 4, it can be seenthat both dissolution methods gave relatively slow release of the drug.The use of a relatively large volume (200 mL) of buffer solution in theconventional USP dissolution method resulted in a higher total amount ofthe released drug, which approached the drug load.

In other embodiments a film forming agent, such as Kollicoat MAE 30 DP,may be mixed with the metakaolin and zolipdem tartrate prior to theaddition of the sodium silicate solution and water so as to decrease thedissolution rate of the active pharmaceutical ingredient from theresultant homogeneous layer of composition in different media such as,for example, low pH, ethanol and hot water.

EXAMPLE 2 Fentanyl-Containing Pellets for Transdermal Drug Delivery

Fentanyl base (MacFarlan and Smith, Edinburgh, UK), Eudragit L100-55(Evonik industries, Germany), kaolin (Al₂Si₂O₅(OH)₄), fumed silica(SiO₂, 7 nm particle size) and reagent grade sodium hydroxide (NaOH)were purchased from Sigma-Aldrich (Stockholm, Sweden).

Metakaolin was prepared by heating the kaolin at 800° C. for two hours.Waterglass was prepared by dissolving 24.398 g of NaOH and 26.306 g ofSiO₂ into 50 mL of distilled water.

Dry materials (metakaolin, Eudragit and fentanyl) were mixed and thenthe waterglass added in a glass mortar until a homogeneous paste wasformed. The paste was applied to a Teflon mould with holes to makecylindrical pellets (1.5×1.5 mm or 1×1 mm, diameter×height). The mouldswere placed in an oven set at 37° C. oven (100% relative humidity (RH))for 48 hours. After the synthesis was complete, the samples wereair-dried for one day and released from the moulds.

Two differently-sized sets of pellets were prepared, starting with:

-   (a) 8 g of metakaolin, 1.0019 g of Eudragit, 0.2401 g of fentanyl    and 14.04 g of the waterglass (providing 11.067 mg of fentanyl per    gram of 1×1 mm pellets); and-   (b) 4 g of metakaolin, 0.50068 g of Eudragit, 0.12033 g of fentanyl    and 6.03 g of the waterglass (providing 11.945 mg of fentanyl per    gram of 1.5×1.5 mm pellets).

Zolpidem-containing pellets were also prepared using essentially thesame process (3 sets of 1.5×1.5 mm pellets containing 1.862 mg, 0.878 mgand 0.158 mg, respectively, of zolpidem in 150 mg of pellets, and oneset of 1×1 mm pellets containing 1.862 mg of zolpidem in 150 mg ofpellets).

1. An abuse-resistant transdermal drug administration device comprisinga drug delivery element defining a contact surface for location, in use,against a patient's skin, the drug delivery element including asustained-release pharmaceutical composition comprising one or moreactive pharmaceutical ingredients co-formedly interspersed within poresof a solid, continuous network comprising a carrier material andpossessing a high mechanical strength, wherein said one or more activepharmaceutical ingredients includes a substance that is open to abusepotential.
 2. A transdermal drug administration device according toclaim 1 wherein the carrier material is based on one or more ceramicmaterials.
 3. A transdermal drug administration device according toclaim 2 wherein the ceramic material is an aluminium silicate or acalcium aluminate.
 4. A transdermal drug administration device accordingto claim 2 wherein the ceramic material is a halloysite.
 5. Atransdermal drug administration device according to claim 1 wherein thecarrier material is based on one or more geopolymeric materials.
 6. Atransdermal drug administration device according to claim 1 wherein thedrug delivery element is formed from pellets of the composition embeddedin a patch matrix.
 7. A transdermal drug administration device accordingto claim 1 wherein the drug delivery element is formed from particles ofthe composition embedded in a patch matrix.
 8. A transdermal drugadministration device according to claim 6 wherein the compositionfurther includes a pelletisation aid material.
 9. A transdermal drugadministration device according to claim 8 wherein the pelletisation aidmaterial is microcrystalline cellulose.
 10. A transdermal drugadministration device according to claim 1 wherein the drug deliveryelement is formed from a homogeneous layer of the composition.
 11. Atransdermal drug administration device according to claim 10 wherein thecontact surface of the drug delivery element is substantially flat. 12.A transdermal drug administration device according to claim 10 whereinthe contact surface of the drug delivery element is moulded to define anarray of microscopic protrusions.
 13. A transdermal drug administrationdevice according to claim 12 wherein the contact surface of the drugdelivery element is moulded to define an array of microscopic pyramidalprotrusions.
 14. A transdermal drug administration device according toclaim 10 wherein the contact surface of the drug delivery element ismoulded to define an array of micro-needles.
 15. A transdermal drugadministration device according to claim 1 wherein the compositionfurther includes a film forming agent co-formedly interspersed withinthe pores.
 16. A transdermal drug administration device according toclaim 15 wherein the film forming agent is an enteric coating material.17. A transdermal drug administration device according to claim 16wherein the film forming agent is a copolymer derived from methacrylicacid and ethyl acrylate or a neutral methacrylic polymer with with-acidor alkaline groups.
 18. A transdermal drug administration deviceaccording to claim 28 wherein the one or more active pharmaceuticalingredients includes an opioid analgesic.
 19. A transdermal drugadministration device according to claim 28 wherein the opioid analgesicis a morphinan derivative, a benzomorphan derivative, aphenylpiperidine, a phenylheptamine, an open chain compound, adiphenylpropylamine derivative, a mixed agonist/antagonist or anothersynthetic opioid.
 20. A transdermal drug administration device accordingto claim 19 wherein the opioid analgesic is selected from morphine,codeine, thebaine or a Diels-Alder adduct thereof, diamorphine,hydromorphone, oxymorphone, hydrocodone, oxycodone, etorphine,nicomorphine, hydrocodeine, dihydrocodeine, metopon, normorphine,N-(2-phenylethyl)normorphine, racemorphan, levorphanol,dextromethorphan, levallorphan, cyclorphan, butorphanol, nalbufine,cyclazocine, pentazocine, phenazocine, pethidine (meperidine), fentanyl,alfentanil, sufentanil, remifentanil, ketobemidone, carfentanyl,anileridine, piminodine, ethoheptazine, alphaprodine, betaprodine,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, diphenoxylate, loperamide,methadone, isomethadone, propoxyphene, levomethadyl acetatehydrochloride, dextromoramide, piritramide, bezitramide,dextropropoxyphene, buprenorphine, nalorphine, oxilorphan, tilidine,tramadol, allylprodine, benzylmorphine, clonitazene, desomorphine,diampromide, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethylmethylthiambutene, ethylmorphine, etonitazene, hydroxypethidine,levophenacylmorphan, lofentanil, meptazinol, metazocine, myrophine,narceine, norpipanone, papvretum, phenadoxone, phenomorphan,phenoperidine, propiram and dezocine.
 21. A transdermal drugadministration device according to claim 20 wherein the opioid analgesicis selected from the group consisting of buprenorphine, alfentanil,sufentanil, remifentanil, fentanyl, and pharmaceutically-acceptablesalts thereof.
 22. A transdermal drug administration device according toclaim 21 wherein the opioid analgesic is fentanyl or apharmaceutically-acceptable salt thereof.
 23. A transdermal drugadministration device according to claim 14, wherein the one or moreactive pharmaceutical ingredients is a peptide or a protein. 24-26.(canceled)
 27. A method of treatment of pain, which method compriseslocating a contact surface of a drug delivery element of a transdermaldrug administration device according to claim 19 against the skin of apatient suffering from, or susceptible to, such a condition.
 28. Atransdermal drug administration device according to claim 1 wherein theone or more active pharmaceutical ingredients includes a substance thatis useful in the treatment of a disease or disorder selected from thegroup consisting of acute or chronic pain, attention deficithyperactivity disorders (ADHD), anxiety and sleep disorders, or whereinthe one or more active pharmaceutical ingredients includes a growthhormone or an anabolic steroid.
 29. A transdermal drug administrationdevice according to claim 21 wherein the opioid analgesic isbuprenorphine or a pharmaceutically-acceptable salt thereof.